ABSTRACT Preterm birth (PTB) complicates one in six pregnancies in the Global South and kills one million newborns per year. Maternal HIV is among the most common serious complications of pregnancy in many settings and is associated with a higher risk of PTB. As combination antiretroviral therapy (ART) has become available to an ever-growing number of pregnant women around the world, perinatal HIV transmission rates have plummeted, but a new complication has emerged. ART in pregnancy appears to increase the risk of PTB even beyond that attributable to HIV infection itself. Antenatal vaginal progesterone (VP) has been found in randomized trials to reduce the risk of PTB among women with a prior preterm birth or sonographic evidence of cervical shortening; it is standard of care for this latter indication in the United States. We hypothesize that VP might prevent PTB among women receiving ART in pregnancy. However, we are concerned about the feasibility of a full-scale efficacy trial, given recent reports from HIV microbicide and pre-exposure prophylaxis studies suggesting low adherence among women randomized to receive vaginal study drug. In this application, we propose to study the feasibility of a trial of VP to prevent PTB among women receiving ART in pregnancy (AIM 1). The trial will screen women with ultrasound biometry and offer enrollment prior to 24 weeks gestation. A total of 140 women will be randomly allocated in a 1:1 ratio to daily self-administration of either VP or matched placebo. The trial?s primary outcome will be adherence, defined as the proportion of participants who achieve 80% use of study product. We will assess adherence objectively with a validated dye stain assay (DSA) that can reliably confirm vaginal insertion among returned single-use VP applicators. We will also measure study uptake (proportion of women who agree to participate in the trial if offered), retention (proportion of participants who remain in the trial until delivery), and preliminary efficacy (difference in the rates of birth prior to 37 weeks between the randomization groups). In a set of concurrent qualitative activities, we will seek a nuanced understanding of the personal, social, and structural barriers to trial participation and adherence to study product (AIM 2). We will invite women who decline enrollment in the trial to participate in semi-structured interviews (SSIs) to assess perceived risk of PTB, desire for an intervention proposed to prevent PTB, attitudes towards VP, and barriers to trial participation. We will then invite women enrolled in the study to participate in longitudinal SSIs to explore factors affecting trial retention and adherence to a daily self-administered vaginal product.